Compositions and methods of treating bladder cancer

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating bladder cancer. The above composition contains an effective amount of valrubicin and dimethyl sulphoxide, as well as polyethoxylated castor oil or one or more substances specified in trimethyl chitosan, mono-N-carboxymethyl chitosan, N-diethylmethyl chitosan, sodium caprylate, cytochalasin B, IL-1, polycarbophil, Carbopol 934P, N-sulphate-N,O-carboxymethyl chitosan, Zonula occludens toxin, 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine, and represents a dosage form for intra-bladder administration by instillation. The invention also refers to liposomal pharmaceutical compositions containing valrubicin, and methods of treating bladder cancer involving administering the above compositions.

EFFECT: invention reduces bladder irritation and increases the clinical effectiveness in bladder cancer.

12 cl, 3 dwg, 3 tbl, 1 ex

 

The technical field to which the invention relates.

The present invention relates primarily to the field of cancer therapy. Specifically, presents therapy of malignant tumors developing in the hollow structure of the patient's body, such as bladder, colon, mouth and stomach.

The level of technology

Tumors in the bladder, usually develop as precancerous lesions and can turn into invasive cancer. Some go to metastatic growth. The most common tumor of the urinary bladder is a transitional cell carcinoma of epithelial origin. Patients with superficial cancer of the bladder have a favorable prognosis, but deep invasion into the underlying musculature reduces the five-year survival rate of approximately 50%.

Surgery is the main treatment method. The degree of surgical intervention depends on the pathological stage of the disease. The disease at an early stage, as a rule, subjected to treatment with intravesical chemotherapy and transurethral resection. Locally invasive disease can be treated only with radical cystectomy and monotagari. Surgery is often accompanied by auxiliary inside the gallbladder introduction of chemotherapy or immunotherapy agent to reduce the incidence and severity of cancer recurrence or in the same or in another place of the bladder wall. Radical (curative) radiation therapy is usually applied to patients with bladder cancer who are not candidates for surgical intervention. For superficial disease at an early stage, chemotherapy is used intravesical (directly into the bladder) for the concentration of the drug in the site of the tumor and to exclude the presence of any remaining after resection of the tumor mass. Chemotherapy can also be used in the treatment of advanced stage bladder cancer.

One such chemotherapeutic agent used to treat bladder cancer, is Valstar® (Valstar®). Valstar® is a composition valrubicin in ethanol, which is installed in the bladder in the treatment of malignant neoplasms of the bladder. For destruction of tumor cells, the drug can be used instead of, or after transurethral resection of the bladder. However, it is known that such compositions are annoying for some patients, so they are removed from the bladder to achieve sufficient efficiency. Thus, for the introduction of valrubicin necessary media, reduces irritation and increases the effectiveness of the treatment.

The invention

In one aspect, compositions and methods of treatment the Oia bladder cancer include intravesical dosage forms antitumor agent. In another aspect, features a pharmaceutical composition comprising an effective amount of an antitumor agent and dimethyl sulfoxide in intravesical dosage form. In some embodiments, the effective amount valrubicin is about 5-100 mg/ml, about 10-90 mg/ml, about 15-80 mg/ml, about 20-70 mg/ml, about 25-70 mg/ml, about 30-60 mg/ml, about 35-50 mg/ml, or about 35 to 45 mg/ml In some embodiments, the pharmaceutical composition additionally includes one or more amplifiers chemical penetration, selected from ethanol, ISO-propanol, dimethylacetamide, dimethylformamide, decelerated, 2-pyrrolidone, N-ethyl-2-pyrrolidone, capric acid, linoleic acid, urea, sodium dodecyl sulfate, sodium lauryl sulphate and mixtures of two or more of these compounds. In other embodiments, the effective amount valrubicin and dimethyl sulfoxide enough for the treatment of bladder cancer.

In some embodiments, the pharmaceutical compositions include an agent for contact opening. In some embodiments, the material for the contact opening can be a trimethyl-chitosan, moho-N-carboxymethylchitosan, N-diethylethylene, sodium katrinasacay, cytochalasin B, IL-1, polycarbophil, carbopol 934P, N-sulfate-N,O-carboxymethylchitosan, toxin, Zonula occludens, 1-Palmitoyl-2-glutaryl-sn-glice is about-3-phosphocholine, and mixtures of any two or more of these compounds. The material for the contact opening may be present in the composition in an amount of about 1-15 wt.% the volume of dosage forms.

In some embodiments, the pharmaceutical compositions include polyethoxysiloxane castor oil. According to other embodiments polyethoxylated castor oil can be cremophor. In some embodiments, cremophor and dimethyl sulfoxide represented in equal numbers. In some embodiments, the pharmaceutical compositions include an agent for contact opening. The material for the contact opening can be a trimethyl-chitosan, mono-N-carboxymethylchitosan, N-diethyl-methylcytosine, sodium katrinasacay, cytochalasin B, IL-I, polycarbophil, carbopol 934P, N-sulfate-N,O-carboxymethylchitosan, toxin, Zonula occludens, 1-Palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine, and mixtures of any two or more of these compounds.

In some embodiments, the pharmaceutical compositions include mucin-degrading compound. In some embodiments, the mucin-degrading compound selected from the group consisting of: trypsin, hyaluronidase, preteenlolita and norepinephrine.

In some embodiments, the pharmaceutical composition includes bioadhesives or mucoadhesive agent. In some embodiments, mucoadhesive agent present is the focus of a polyacrylic acid. In some embodiments, the pharmaceutical composition additionally contains an ionic or non-ionic surfactant, polyvinylpyrrolidone, alginates, polyacrylic acid or a mixture of any two or more of these compounds. Typical ionic and non-ionic surfactants include polyoxyethylene derivatives of castor oil, the block copolymers tylenchida and propylene oxide, esters of sorbitol and fatty acids or a mixture of any two or more of these compounds. Typical polyacrylic acid include carbomer 934P, carbomer 940, carbomer 941, carbomer 974P, carbomer 980, carbomer 1342, polycarbophil, polycarbophil calcium or a mixture of any two or more of these compounds.

In another aspect, features a pharmaceutical composition comprising an effective amount valrubicin and 2-hydroxy-propyl-β-cyclodextrin in intravesical dosage form. In some embodiments, the amount of 2-hydroxy-propyl-β-cyclodextrin is about 1-5 wt.% the volume of dosage forms. In some embodiments, the pharmaceutical composition additionally contains a substance for opening tight contacts. In some embodiments, the agent for open contacts is a trimethyl-chitosan, mono-N-carboxymethylchitosan, N-diethyl-methylcytosine, sodium katrinasacay, cytochalasin is B, IL-I, polycarbophil, carbopol 934P, N-sulfate-N,O-carboxymethylchitosan, toxin, Zonula occludens, 1-Palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine, or a mixture of any two or more of these compounds. In some embodiments, the pharmaceutical composition also includes bioadhesives or mucoadhesive agent. In some embodiments, mucoadhesive agent is a polyacrylic acid.

In another aspect, features a pharmaceutical composition comprising a liposomal dosage form containing an effective amount included in the liposome valrubicin, while liposome containing at least one lipomatous substance selected from the group consisting of: phosphatidylcholine and phosphatidylethanolamine. In some embodiments, lipomatous substance contains phosphatidylcholine in an amount of about 4-8 wt.%. In other embodiments, the pharmaceutical composition comprises cholesterol in an amount of about 0.5 to 2 wt.%. In some embodiments, the pharmaceutical composition includes one or more sphingolipids, which are D-glucosyl-β1-1 ceramic (C8); D-glucosyl-β1-1'-Ceramic (C12); D-glucosyl-β1,1'N-Palmitoyl-D-urethrostenosis; D-galactosyl-β1-1 ceramic (C8); D-galactosyl-β1-1 ceramic (12); D-galactosyl-β1-1'-N-nervonic-D-urethrostenosis; or D-glactose-β1-1' ceramide (C8); and D-glactose-β1-1 ceramic (C12), in an amount of about 1 to 6 mass%. In some embodiments, lipomatous substance contains phosphatidylethanolamine in an amount of about 2-8 wt.%. In other embodiments, the pharmaceutical composition includes phosphatidylinositol in an amount of about 1-5 wt.%, in some other embodiments, the pharmaceutical composition comprises oleic acid in an amount of about 0.5 to 1 wt.%. In other embodiments, the pharmaceutical composition comprises cholesterol in an amount of about 0.5 to 2 wt.%. In some embodiments, the pharmaceutical composition includes diglyceride succinic acid in an amount of about 3-4 wt.%. In some embodiments, the pharmaceutical composition comprises oil. Such oil may be included as non-limiting examples of carthamin, triacetyluridine and cottonseed oil. In some embodiments, the pharmaceutical composition includes power penetration. In some embodiments, the amplifier penetration represents oleic acid, capric acid, linoleic acid, urea, sodium dodecyl sulphate, sodium lauryl sulphate, or a mixture of any two or more of these compounds.

In another aspect, features a pharmaceutical composition comprising an effective amount included in the emulsion valrubicin; where the emulsion includes at least one forming the emulsion substance selected from phosphatidylcholine, phosphatidylethanolamine oil. In some embodiments, the oil is selected from the group consisting of: certamina, triacetyluridine and cottonseed oil. In other embodiments, the pharmaceutical composition further includes an amplifier penetration. In some embodiments, power penetration is a sulfoxide, oleic acid, capric acid, linoleic acid, urea, sodium dodecyl sulphate, sodium lauryl sulphate, or a mixture of any two or more of these compounds.

In another aspect, features a method of treating bladder cancer comprising introducing a composition containing an effective amount valrubicin and dimethylsulfoxide. In some embodiments, the composition is administered after intravesical transretinol resection of the bladder.

In another aspect, features a method of treating bladder cancer, including the introduction of liposomal dosage forms comprising an effective amount included in the liposome valrubicin, where the liposome comprises at least one lipomatous substance selected from phosphatidylcholine and phosphatidylethanolamine.

In another aspect, features a method of treating bladder cancer, including the introduction of emulsion dosage form containing an effective amount included in the emulsion valrubicin; where the emulsion includes, for less than the least one forming the emulsion substance selected from phosphatidylcholine, phosphatidylethanolamine and oil. In some embodiments, the oil is selected from the group consisting of: certamina, triacetyluridine and cottonseed oil. In other embodiments, the pharmaceutical composition further includes an amplifier penetration. In some embodiments, power penetration is a sulfoxide, oleic acid, capric acid, linoleic acid, urea, sodium dodecyl sulphate, sodium lauryl sulphate, or a mixture of any two or more of these compounds.

Brief description of drawings

Fig.1 is a graph comparing the average of inflammation as a result of the negative control in the form of a composition of the salt solution, positive control, in the form of a composition Valstar and compositions according to one embodiment in the form of valrubicin/DMSO.

Fig.2 is a graph comparing the average indicators of inflammation in the composition Valstar, composition valrubicin/DMSO and valrubicin/liposomal compositions according to some embodiments.

Fig.3 is a graph comparing the average of inflammation as a result of tracks 4, 9, 11 and 12 according to some embodiments.

The implementation of the invention

Before will be on isany the present compositions and methods, it should be borne in mind that they are not limited to a specific method, composition or methodology, because they can change. Also keep in mind that used in the description of the terminology is intended solely for the purpose of describing a particular variants of the embodiments and should not be construed as limiting. While not defined otherwise, all technical and scientific terms used herein have the same meaning as that usually understood by the person skilled in the art. All publications, patent applications, issued patents, and other documents referenced in this description are incorporated herein by reference, that each individual publication, patent application, issued patent, or other document in full. Definitions contained in the text included by reference, may not be extended if it is contrary to the definitions in the present description.

Compounds described in this application, may contain an asymmetric center and thus can exist as enantiomers. In the case where the compounds possess two or more asymmetric centers, they may additionally exist as diastereomers. Connections include all possible stereoisomers, in the form of essentially pure, split the s enantiomers, their racemic mixtures, as well as mixtures of diastereomers. The formula shown without a definitive stereochemistry at certain positions. Connections include all stereoisomers of such formulas and their pharmaceutically acceptable salts. Diastereoisomer pair of enantiomers can be separated, for example by means of fractional crystallization from an appropriate solvent, and the thus obtained pairs of enantiomers can be separated into individual stereoisomers by using the appropriate methods, for example using an optically active acid or base as a separating agent or on a chiral HPLC column. Alternatively, any enantiomer or diastereoisomer of compounds of General formula can be obtained by using stereospecific synthesis using optically pure starting substances known configuration.

In the description given hereinafter, is widely used a number of terms.

In this application provides definitions to facilitate understanding of various embodiments. The terms defined below, more fully defined by reference to the description as a whole. Units, prefixes and symbols can be identified in their accepted in the SI system form.

Used (used) here, the term "about" means plus or minus 10% of the numerical value of the number, the place with which the term is used.

Used herein, the term "introduction" or "introduction" in combination with the medicinal product, means the administration of a medicinal product directly into or onto the target tissue or administration of a medicinal product to a patient, whereby the drug is positively impacts the tissue to which it is intended. Thus, used here, the term "introduction" in combination with an antitumor agent, may include as non-limiting examples of the presence antitumor agent into or onto the target tissue, or the presence antitumor agent in the body of the subject, for example, by intravesical injection.

Used here, the term "controlled release" refers to a composition or vehicle designed for continuous release of certain therapeutically effective drug or other active agent, such as an antitumor agent over an extended period of time, with the result of reducing the duration of treatment required to achieve the desired therapeutic effect. As such, the composition of the controlled release will reduce the duration of treatment required to achieve a target therapeutic effect in the treatment of RA is and or prevent cancer recurrence. Compositions with controlled release reach the required pharmacokinetic profile of the patient, preferably when the onset of release of the active agent, essentially, takes place immediately after placing in a delivery environment, followed by a constant, slow, preferably, zero order or approximately zero order release of the active agent. Controlled release includes some constant release of the active agent from the dosage of the composition to such an extent that a therapeutically beneficial level of active agent was maintained for an extended period of about one day to about one week, from one week to about one month, more preferably from about one month to about two months.

The term "inhibition" includes the introduction of compounds to prevent the onset of symptoms, or improvement of symptoms, or eliminating the disease, pathological condition, or disorder.

The terms "patient" and "object" refers to all animals, including humans.

Examples of patients or objects of treatment include humans, cows, dogs, cats, goats, sheep and swine.

Using the phrase "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the ima with the other ingredients of the composition and must not harm their recipient.

The term "pharmaceutically acceptable salts, esters, amides and proletarienne means" when used in this application denotes carboxylate salts, amino acids, esters, amides and proletarienne means of connection, which, within reasonable medical decisions, are suitable for use in contact with the tissues of patients without non-specific toxicity, irritation, allergic response and the like, in accordance with a reasonable ratio of benefit/risk, and are effective for their intended use, as well as zwitter-ion form compounds where possible.

The term "proletarienne agent" refers to compounds that are rapidly transformed in vivo to obtain the parent compounds of the formula above, for example, by hydrolysis in blood. A full discussion is presented in the publications of T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol.14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference.

In addition, the compounds can exist in resolutiony, as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In General, the solvated forms are considered equivalent to the valence nonsolvated forms.

The term "salt" refers to relatively non-toxic salts of the compounds obtained by the addition of inorganic and organic acids. These salts can be obtained in situ during the final isolation and purification of the compounds or by a separate entry reacting the purified compound in its free base form with a suitable organic or inorganic acid and by allocating formed so of salt. Typical salts include salts as acetate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerianate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosilata, citrate, maleate, fumarata, succinate, tartrate, naphthalate, nelfinavir, glucoheptonate, lpcomment and laurylsulfate and the like. These may include cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, Tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. ScL, 1977, 66:1-19, which is incorporated herein by reference).

Used here, the term "drug" refers to an agent used to treat, combat, improved the symptoms I, prevent or improve undesirable pathological condition or disease of the patient. In part, embodiments relate to the treatment of bladder cancer or to reduce the recurrence of bladder cancer compared to subjects to whom the drug is not administered.

"Therapeutically effective amount" or "effective amount" of a composition is a certain amount calculated to achieve the target effect, i.e., for reducing or preventing bladder cancer or recurrence of bladder cancer. Provided the activity includes both medical therapeutic and/or prophylactic treatment, as appropriate. The specific dose of a compound, administered to obtain therapeutic and/or prophylactic effects will, of course be determined by the specific circumstances relating to the patient, including, for example, entered the compound, route of administration and subjected to the treatment of a pathological condition. Although it is clear that the introduced effective amount will be determined by the physician in light of the relevant circumstances, including being treated with a pathological condition, the choice of the introduced compound, chosen route of administration, and therefore, the above dosing intervals in any case not intended for the OTF is to limit the range of dosing. A therapeutically effective amount of a compound usually represents a number, which, when introduced with physiologically acceptable auxiliary composition is sufficient to achieve effective total concentration or local concentration in the tissue.

The terms "treat", "treated" or "treating" when used in this application indicate therapeutic treatment and prophylactic or prevention measure, the purpose of which is the avoidance or mitigation of undesirable physiological pathological condition, disorder or disease, or obtain beneficial or target clinical outcomes. Useful or target clinical results include, as non-limiting examples of improvement of symptoms; reducing pathological condition, disorder or disease; stabilization (i.e., not worsening) of the pathological condition, disorder or disease; delay symptoms or slow the progression of the pathological condition, disorder or disease; improving the status of the pathological condition, disorder or disease; remission (partial or complete), detektiruya or not detektiruya, or rehabilitation or improvement of the pathological condition, disorder or disease. Treatment includes a call to the Kli is significant automatic response without excessive levels of side effects. The treatment also includes prolonging survival as compared to expected survival if untreated.

Compositions and methods

We offer pharmaceutical compositions possess activity as anti-tumor agents for the treatment of bladder cancer patients. In one aspect, the pharmaceutical compositions contain antitumor agent (neoplastic agent - NA) and power of penetration. In one embodiment, the composition contains an effective amount valrubicin and power of penetration in the form of dimethyl sulfoxide (DMSO). In other embodiments, the composition contains an effective amount valrubicin, power penetration and Supplement.

Suggested ways to overcome a number of barriers to the effective delivery of anticancer agent to the wall of the bladder. Specifically, the barriers to effective delivery include (a) mutiney layer, which surrounds the wall of the bladder, (b) short-time interval for which the antitumor agent is able to come into contact with the wall, and (c) the penetration of anticancer agent through the wall of the bladder. Compositions and methods adequately treated tumor cells in the case when can be injected into the underlying musculature.

In various embodiments, the anticancer agent or oncologist is static agent comprises an antiproliferative agents, mitomycin C, valrubicin and doxorubicin, Taxol and BCG. In the preferred embodiment, the anticancer agent is valrubicin. Valrubicin (N-triftoratsetilatsetonom-14-valerianate, Valstar®) is a chemotherapy drug used in the treatment of bladder cancer. Valrubicin is a semisynthetic analogue of anthracycline doxorubicin and is administered by infusion directly into the bladder.

In one embodiment, the pharmaceutical composition comprises an antineoplastic agent and an acceptable power chemical penetration through the skin. Amplifiers chemical penetration destroy the ordered structure of intracellular lipid bilayers (lipophilic path), and the intracellular environment (hydrophilic path). There are many collections of chemical enhancers, including alcohols (ethanol, isopropanol), amines and amides (dimethylacetamide, dimethylformamide), sulfoxidov (decelerated, dimethylsulfoxide (DMSO)), pyrrolidone (2-pyrrolidone, N-ethyl-2-pyrrolidone), fatty acids (capric acid, linoleic acid), urea and unsaturated cyclic urea, surfactants (sodium dodecyl sulphate, sodium lauryl sulphate) and others (see Percutaneous Permeation Enhancers, CRC Press, 1995).

In specific embodiments, the amplifier chemical proniknout who I am compatible with valrubicin. In a specific embodiment, DMSO is an acceptable power chemical penetration through the skin. DMSO is the preferred amplifier penetration through the skin, because (a) it was approved for use for installation into the bladder (Rimso 50, PDR, 58th Edition, 2004, p.1215), and (b) it can reduce the discomfort associated with rapidly evaporating ethanol compositions currently available. In addition, DMSO will carry some amount valrubicin in the underlying muscles without affecting the amount that reaches the General circulation. Due to the hydrophilic nature of the tissues of the bladder, valrubicin will be deposited in contact with them. Accordingly, it is expected that compositions containing valrubicin and DMSO will kill tumor cells that have penetrated into the underlying muscle.

As noted above, the composition may also contain additives in addition to valrubicin and DMSO. In some embodiments, such additives include ionic and non-ionic surfactants, such as polyoxyethylene derivatives of castor oil, the block copolymers tylenchida and propylene oxide, esters of sorbitol and fatty acids; polyvinylpyrrolidone; alginates; and polyacrylic acid.

Polyoxyethylenated derivatives of castor oil include as non-limiting examples of policies longitudinaldata or castor oil polyoxyl 35 (Cremophor®EL, BASF Corp.), polyoxyethylenesorbitan (Cremophor®RH 40 (peg-40 hydrogenated castor oil), Cremophor®RH 60 (polyethyleneglycol 60 hydrogenated castor oil), BASF Corp). Block copolymers tylenchida and propylene oxide include as non-limiting examples of the polyoxyethylene-polyoxypropylene block copolymers or polyoxyethylene-polyoxypropyleneglycol, such as Poloxamer®124, Poloxamer®188, Poloxamer®237, Poloxamer®388, Poloxamer®407 (BASF Wyandotte Corp.), and things like that. Esters of sorbitol and fatty acids include as non-limiting examples monetary fatty acids and polyoxyethylene (20) sorbitan, for example, polyoxyethylene (20) sorbitan-monooleate (Tween®80, and Polysorbate®80), polyoxyethylene (20) sorbitan-monostearate (Tween®60), polyoxyethylene (20) sorbitan-monopalmitate (Tween®40), polyoxyethylene (20) sorbitan-monolaurate (Tween®20), and the like. Polyacrylic acid can be an alternative known as Carbomer 934P, 940, 941, R, 980, 1342, polycarbophil and calcium polycarbophil (BF Goodrich).

DMSO was used to enhance the penetration of agents into the bladder wall, but the state of the prior art is that prior to filing this application was considered that the introduction of DMSO results in cell death or to fixation of the cells, which can reduce the effectiveness of any hamiota piticescu treatment, which is incorporated by DMSO. For example, Borzelleca et al. (Investigative Urology 6(7), 43-52 (1968)) describes the use of DMSO for the introduction of sodium salicylate in the urinary bladders of rabbits. However, Borzelleca demonstrated that the epithelium of the urinary bladder sensitive to even a five per cent solution DMSO in water, and a twenty-percent solutions of DMSO in water led to severe reactions such as loss of epithelial cells. Id. In absolute DMSO, cells, still normal, was recorded as if to cells was applied histological fixative. Id. Thus, at the time it was expected that DMSO will have the opposite target effects.

In one embodiment, the pharmaceutical composition comprises an antineoplastic agent and an enzyme or compound that degrades mutiney layer covering the wall of the bladder. Mutiney layer covering the bladder wall consists of glucosaminoglycans, hyaluronic acid and chondroitin sulfate, elevated levels are observed in patients with bladder cancer. Not wanting to be limited to any particular mechanism, it is assumed that if mutiney layer is removed, the chemotherapeutic agent can reach the layer of the lumen wall of the bladder and become more effective in the treatment of disease. Enzymes, as well as other compounds, can on gradiosity mutiney layer. Examples include trypsin and enzymes hyaluronidase animal and recombinant. Preteenslut and norepinephrine are other compounds that can also be used.

In one embodiment, the pharmaceutical composition comprises an antitumor agent and bioadhesives or mucoadhesive agent, which will facilitate the formation of at least a monomolecular layer of the composition on the walls of the bladder for an extended period of time. Bioadhesive agents are used to increase the residence time of the dosage form, as well as to improve contact with various absorbent membranes, such as mucous tissue of the bladder wall. Except as platforms for controlled release, bioadhesive polymers themselves can exercise some control the speed and amount of release of the medicinal product and, thus, to contribute to therapeutic benefit of such systems, Bioadhesive Drug Delivery Systems, CRC Press, p.66 (1990)). Typical natural polymers include proteins such as Zein, modified Zein, casein, gelatin, gluten, serum albumin, and collagen; polysaccharides, such as cellulose, dextrans and Polygalaceae acid. Typical synthetic polymers include polyphosphazenes, poly(wine is gross alcohols), polyamides, polycarbonates, polyacrylates, polyalkylene, polyacrylamides, polyalkylene glycols, polyalkylene, polyalkylacrylate, simple polyvinyl esters, complex, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and their copolymers. Examples of suitable polyacrylates include poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyronitrile), poly(hexidecimal), poly(isabellemadelinet), poly(laurenmarie), poly(fenilsalicilat), poly(methyl acrylate), poly(isopropylacetate), poly(isobutylamino) and poly(octadecylsilyl).

The polymers described above can be characterized separately as biodegradable not biodegradable and bioadhesive, polymers that are discussed further below. Typical synthetic degradiruete polymers include PHAs, such as polylactide, polyglycolides and their copolymers, poly(ethyleneterephthalate), poly(butane acid), poly(valeric acid), poly(lactamaseproducing), polyanhydride, polyarteritis and their mixtures and copolymers. Typical natural biodegradable polymers include polysaccharides such as alginate, dextran, cellulose, collagen, chemical derivatives (substitutions, additions of chemical groups, for example, Akilov, and is Kalenov, hydroxylation reactions, oxidations, and other modifications, usually performed by specialists in this field), and proteins such as albumin, Zein, and mixtures thereof and copolymers, both individually and in combination with synthetic polymers. Typically, in vivo these substances degrade or through enzymatic hydrolysis or by the action of water, by means of surface or internal erosion. Examples of biodegradable polymers include ethylene vinyl acetate, poly(meth)acrylic acid, polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinyldene, and their copolymers and mixtures. Hydrophilic polymers and hydrogels tend to possess bioadhesive properties. Hydrophilic polymers that contain carboxyl groups (for example, poly[acrylic acid]) tend to manifest the best bioadhesive properties. The polymers with the highest concentrations of carboxyl groups are preferred in the case when the target is bioadhesive on the soft tissues. Various derivatives of cellulose, such as sodium alginate, carboxymethylcellulose, hydroxyethylcellulose and methylcellulose, also have bioadhesive properties. Some of these bioadhesive substances are water-soluble, while others are hydrogels. Polymers, such as females who inat acetate hydroxypropylmethylcellulose (HPMCAS), trimellitate cellulose acetate (CAT), phthalate cellulose acetate (CAP) phthalate acetate hydroxypropylcellulose (NRCAR), phthalate acetate hydroxypropylmethylcellulose (NRMSE), and phthalate acetate methyl cellulose (MCAP), can be used to enhance the bioavailability of drugs with which they form a complex. As bioadhesive substances for delivery of anticancer agents can be used quickly biodegradable polymers, such as poly(lacticacid), polyanhydride and polyarteritis, whose carboxylic groups are exposed on the outer surface, because of their external surface is exposed to erosion.

In one embodiment, the pharmaceutical composition comprises an antitumor agent and one or more compounds, opening tight contact, to enable neoplastic agent to penetrate into the underlying musculature. Connection opening tight contact, regulate parallelity transport drugs, allowing temporary, rapid and reversible permeability of dense contact in epithelial tissue. One example of such modifiers is 1-Palmitoyl-2-glutaryl-sy-glycero-3-phosphocholine (Nastech Pharmaceutical). Other examples include N-diethylethylene (International Journal of Pharmaceutics 293:83, 2005); Kapral sodium, cytochalasin In (Digestive Diseases and Siences A3: 1547, 1998); IL-1 (J. Immunology 178:4641, 2007); polycarbophil, carbopol 934P, carbomer and trimethylchitosan (Biomaterials 23 (1): 153, 2002 and Pharm. Res 18 (11): 1638, 2001); monocarboxylate chitosan (Adv. Drug Delivery Reviews 52 (2): 117, 2001); N-sulfate-N,O-carboxymethylchitosan (U.S. Patent No. 7265097); and toxin Zonula occludens and fragments (Adv. Drug Delivery Reviews 58:15, 2006). Accordingly, in some embodiments also includes modulators tight contact in combination with chemical enhancers and other excipients, affecting three barrier mentioned above.

In one embodiment, the pharmaceutical composition comprises an anticancer agent in combination with liposomes to stabilize and solubilize the antitumor agent and for its penetration into the bladder wall. Liposomes are phospholipid vesicles, which were developed as systems of drug delivery vehicles to achieve site-specific pharmacological action or the controlled release of drugs, thus strengthening the effectiveness while reducing side effects. If you are not limited by theory, the liposomes can be suitable carriers for the delivery of anticancer agent because (a) they can be put in place to control the release of the antitumor agent, (b) they will protect protiva wholely agent from the biological environment prior to its release, (c) they provide a means to reduce the toxicity of anticancer agent prior to its release, and (d), depending on the lipids, they have the ability to affect specific cells.

Liposomes can be obtained from a variety of amphiphilic lipids and lipid mixtures, such as phospholipids, cholesterol, sphingolipids and triglycerides of fatty acids. For example, suitable liposomal compositions contain a combination phosphatidylethanolamine and phosphatidylinositol together with cholesterol, oleic acid or diglycerides succinate. Additional liposomal compositions contain a combination of phosphatidylcholine and cholesterol together with each of the following sphingolipids: D-glucosyl-β1-1 Ceramica (C8); D-glucosyl-β1-1 Ceramica (C12); D-glucosyl-β1-l'-N-Palmitoyl-O-retroversion; D-galactosyl-β1-1 Ceramica (C8); D-galactosyl-β1-1 Ceramica (C12); D-galactosyl-β1-1'-N-nervonic-O-retroversion; or D-galactose-β1-1 Ceramica (C8); D-galactose-β1-1 Ceramica (C12).

When the hydration of the phospholipid mixture will be organized in a single-layer or multilayer bolognia patterns. However, these mixtures containing phosphatidylethanolamine together with oleic acid or diglycerides succinate, will be organized in such structures at neutral pH. At acidic pH, these patterns will form nebis eunie patterns, which allow membrane fusion (Progress in Lipid Research 39 (2000) 409-460). The layered structure consisting of sphingolipids, will contain a surface coating of carbohydrates, which is expected to be strongly interact and communicate with glycosaminoglycans or mucinosis layer of the bladder. Binding of these liposomes with mucinosis layer will enable directional slow release valrubicin. As these phospholipids consisting of phosphatidylethanolamine, phosphatidylinositol and oleic acid or diglyceride succinate, will contact mucinosis layer due to pentahydroxyflavanone component phosphatidylinositol, the release valrubicin is expected to be more rapid at lower pH in the bladder.

The treatment of the disease or pathological condition may be accompanied by the object to the introduction of the compositions of the antitumor agent, as embodied in this document. The introduction of the compositions may be continuous or intermittent, depending, for example, the physiological state of the recipient, and other factors known to practitioners. The introduction of the compositions can essentially continue for a pre-selected period of time or can be a series of separate doses.

In some embodiments, the pharmaceutical preparations is practical compositions can be used in combination with therapeutic agents one or more, for the treatment of malignant tumors. In one embodiment, the pharmaceutical composition combined with immunotherapy using Bacillus Calmette-guérin (BCG). BCG activates DTH-like immune response local type 1 (ThI), which results in necrosis of the tumor.

In one embodiment, compositions of the antitumor agent is administered directly to a subject to achieve the target response. Enter the amount will vary depending on various factors, including as non-limiting examples of the composition, to a specific disease, the weight, physical condition and age of the subject, to achieve either prevention or treatment. Such factors can be easily determined by a medical practitioner using models of animals or other test systems, which are well known in the prior art.

Typically, the effective amount of the compositions sufficient to achieve a therapeutic or prophylactic effect, varies in the range from about 1 mg to intravesical introduction to about 1000 mg intravesical administration. Preferably, the dosing intervals range from about 50 mg to intravesical introduction to about 500 mg intravesical administration.

An effective amount (e.g., dose) of the compositions of anticancer agents is a, described herein will provide therapeutic benefit without causing the subject has significant toxicity. The toxicity of the compositions of the antitumor agent described herein, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effects is a therapeutic index. Data obtained from these tests using cell cultures and animal studies can be used in the formulation of the dosing interval, which is not toxic for use in humans. The exact composition, route of administration and dosage can be chosen by the physician taking into account the state of the subject. See, e.g., Fingl et al., In: The Pharmacological Basis of Therapeutics, Ch. 1 (1975).

When you get a pharmaceutical composition for injection, preferably together with a pharmaceutically acceptable carrier, diluent or auxiliary substance with the formation of a pharmaceutical composition or a single dosage form. In General, the active ingredients in such compositions comprise from 0.1 to 99.9% by weight of HDMI is tion. The active ingredient for injection may be presented in the form of a powder or as granules; as a solution, suspension or emulsion.

Pharmaceutical compositions containing anti-tumor agents can be obtained using procedures known in the prior art using well known and readily available ingredients. Antineoplastic agents can be incorporated into compositions in the form of solutions suitable for parenteral administration, for example, using intramuscular, subcutaneous or intravenous routes of administration. Pharmaceutical compositions of anti-tumor agents may also take the form of an aqueous or anhydrous solution or dispersion solution, or, alternatively, the form of emulsion or suspension.

The active ingredients may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and can contain prescription agents, such as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredients can be provided in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for Association with a suitable carrier, e.g. sterile pyrogen-free water before use.

Pharmaceutical HDMI is tion can be included as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents, and salts of this type, which is well known from the prior art. Specific, non-limiting examples of carriers and/or diluents that are used in the pharmaceutical compositions include water and physiologically acceptable buffered saline solutions such as phosphate buffered saline solutions pH 7-8.

Suitable carriers for parenteral solutions include water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions, and/or glycols, such as propylene glycol or polyethylene glycols. Solutions for parenteral administration contain the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfate or ascorbic acid, or individually or in combination, are suitable stabilizing agents. Also used citric acid and its salts, and sodium salt of ethylenediaminetetraacetic acid (EDTA). In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl - or propylparaben and chlorbutanol. Suitable pharmaceutical carriers are described in "Remington''s Pharmaceutical Sciences, a standard reference PU is likely in this field.

In addition, to control the duration of action can be applied to standard pharmaceutical methods. They are well known in the art and include drugs controlled release and may include suitable macromolecules, such as polymers, polyesters, polyaminoamide, polyvinyl, pyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose or preteenslut. The concentration of macromolecules as well as the methods of incorporation may be regulated with the aim of supervised release. In addition, the agent can be incorporated into particles of a polymeric material such as polyesters, polyaminoamide, hydrogels, poly(lactic acid) or copolymers of ethylene vinyl acetate. In addition to enabling these agents can also be used to capture compounds in microcapsules.

Accordingly, the pharmaceutical compositions can be delivered via various routes and to various locations of the body of a mammal to achieve a specific effect. The person skilled in the art it is known that, although it can be used by more than one route of administration, a particular route can provide a more rapid and more effective reaction than any other. Local and systemic delivery may be accomplished by the installation, including the application or introduction of the composition into the body cavity, ingal the tion or insufflation aerosol, or by parenteral introduction, containing intramuscular, intravenous, peritoneal, subcutaneous, intradermal, and local introduction, in the preferred embodiment, a composition for intravesical introduction to the subject, i.e., for introduction into the bladder.

Examples of such carriers or diluents include as non-limiting examples of water, saline solution, solutions, ringer's solution, dextrose and 5% human serum albumin. As described above, can also be used liposomes and non-aqueous media, such as fixed oils. The use of such media and compounds for pharmaceutically active substances is well known in the prior art. Except when any suitable environment or connection not compatible with anticancer agents, it is supposed to use in their compositions. Also in the composition may include additional active compounds.

Thus, for understanding of the present embodiments, described in General terms, reference is made to the following examples, presented for illustrative purposes and not intended to be any limitation of the present technology.

Examples

The following table additionally illustrate various embodiments and should not be construed as limiting. Tables represent the enumeration of compositions walrus is the Qing.

Table 1
Composition valrubicin containing DMSO
ConnectionTrack
Valstar®123456
Valrubicin (mg)40404040404040
Ethanol (ml)0,50
DMSO (ml)0,500,250,250,250,25
Cremophor EL (ml)0,50 0,50
Polysorbate 80 (ml)0,750,750,750,750,50
Polyacrylic acid (mg)28
Polyvinylpyrrolidone K-17 (mg)113
Sodium alginate (mg)14
Polyethylene glycol 400(ml) 0,50
Poloxamer 407 (mg)525
Saline solution (ml)2,752,752,752,75

Table 2
Selected lipid composition
No HDMI.RatioAO(a)PC(b)(mg/ml)Lyso-PC (mg/ml)(c)DOTAP (mg/ml)(d)Glycolipid (mg/ml)(e)Walrus. (mg/ml)
7DOPC/Lisa-oleoyl-MS (molar ratio 9/1)No79,7644 10
8Soy RS-Lisa-soy-PC (molar ratio of 7/3)Yes67,322,112,1
9Soy RS-Lisa-soy-PC/DOTAP (molar ratio 7/3/1)Yes55,422,69,3611,2
10Soy PC-litho-No58,0of 21.99,5011,2

No HDMI.RatioAO(a)RS(b)(mg/ml)Lisa-RS (mg/ml)(C)DOTAP (mg/ml)(d)Glycolipid (mg/ml)(e)Walrus. (mg/ml
soy-PC/DOTAP (molar ratio 6/3/1)
11Soy RS-Lisa-soy - RS/Glycolipid A (molar ratio 69/30/1)Yes69,520,9N/a11,7
12Soy RS-Lisa-soy - RS/Glycolipid B (molar ratio 69/30/1)Yes70,021,0N/a11,5
13Soy RS-Lisa-soy - PC/DOTAP/a Glycolipid (molar ratio 59/30/10/1)Yes59,521,09,41N/a11,2
(a)Antioxidants are tocopherol and ascorbate-6-palmitate at 0.1 wt.% each of the CSOs to the total content of lipids.
(b)PC=phosphatidylcholine
DOPC=dioleoylphosphatidylcholine
Soy PC=soybean phosphatidylcholine
(C)Lisa-RS=1-acyl-2-hydroxy-sn-glycero-3-phosphocholine
(d)DOTAP=1,2-diacyl-3-dimethylammonium-propane (DAP)
(e)Glycolipid - glycolipid, A = D-glucosyl-β1-1'-N-dodecanoyl-D-Erythro-sphingosine (C12 β-D-glucosyl ceramide); glycolipid = D-lactose-β1-1'-N-dodecanoyl-D-Erythro-sphingosine (C12 β-D-lactose ceramide)
N/a indicates that the number of glycolipid was not defined in the expression mg/ml

Example 1

In this example, various compositions identified in the tables above and below, was instillirovti in the urinary bladders of rats. Rats were then scored intervals of time, and collected blood and urinary bladders. Blood was analyzed for total penetration valrubicin. Bladders were analyzed for inflammation by scoring the bladder by five parameters: the blockage of veins, edema, destruction of the epithelium, hemorrhage, and cellular infiltration, which has been evaluated is on a scale from zero to ten, where number between them describe the various degrees of the measured parameters. For edema zero corresponds to the absence of edema, while ten matches severe focal edema, which includes the entire bladder. For the blockage of veins, zero corresponds to the absence of blockage of the veins, while ten matches all visible venous vessels, which greatly expanded. For cell infiltration, zero corresponds to the absence of cellular infiltration, while ten matches very serious cell infiltration, suggesting infection (presence of neutrophils). For the destruction of the epithelium, the zero corresponds to the absence of epithelial destruction, while ten corresponds to the loss of large areas of epithelium. For hemorrhage zero corresponds to the absence of hemorrhage, while ten corresponds to the absolute extensive hemorrhage. Five individual numerical scores are then summed to obtain the total scoring of inflammation for each animal. Then the number of animals used for any particular composition, were included to determine the average scoring of inflammation for this composition. Lower scoring of inflammation, believed to be associated with a lower amount of irritation of the urinary n is Syria.

Table 3
The results of the test for inflammation/irritation
# Songs.1'Intelligence. Sol. Rest.2Tested AnimalsThe average value for each parameter, based on #of AnimalsA composite score of inflammation
SVAboutKIERToAverageSTD. Off.STD. Have been recovered. medium
The control - SalineNo71,94,02,02,009,9the 4.71,9
Valstar®1:178,086 8,78,06,74012,8the 5.7
Valstar®1:2,7565the 4.76,2the 5.74,01,522,06,77,2
11:162,23,72,71,80,210,55,82,6
11:2,75662,75,02,01,30,511,53,71,6
4No74,657 4,62,61,720,3the 10.14,5
8No53,27,4of 5.43,40,019,45,12,3
9No54,64,83,43,20,016,010,84,8
11No476,06,53,32,80,819,08,34,1
12No386,97,4 4,42,91,023,220,211,7
1See tables 1 and 2 for the content of the songs.
2'Intelligence. Sol. rest. Indicates the dilution of the salt solution composition together with a saline solution on the basis of the ratio of volume to volume, for example, the volume of the composition: the amount of salt solution.
3Average point score of inflammation represents the average value of the total scoring of inflammation for each animal tested.
STD. off. is an abbreviation for standard deviation.
STD. have been recovered. medium is an abbreviation for standard error of the mean.

4Abbreviations parameters: SV refers to the blockage of veins; means swelling; KI denotes cell infiltration; re denotes the destruction of the epithelium; and K denotes the bleeding.
5Had testireba the ü seven animals, but they found the infection, and the results were excluded.
6Had to test seven animals, but one died during the test and his bladder was not tested.
7Had to test seven animals, but one died during the test and his bladder was not tested. The animal was approximately 20 grams less than the control animal, and thus, compositions 4, 8, and 9, in which at the time of installation was used anesthetic, could be too much for him.
8Had to test seven animals, but two died during the test and their bladders were not tested. Animals were approximately 20 grams less than the control animal, and thus, compositions 4, 8, and 9, in which at the time of installation was used anesthetic, could be too much for them.

Fig.1-3 illustrate graphically the results presented in table 3. Fig.1 illustrates graphically the inflammation of the urinary bladders of rats (animals) as a result of the installation of the indicated composition. A simple salt solution results in the average ball the Oh assessment of inflammation, component of approximately 10. Standard composition Valstar® with dilution with saline 1:1, results in a much higher scoring of inflammation, which constitutes approximately 40. Introduction to composition 1 dilution with saline 1:1 results in scoring of inflammation, is approximately equal to that found during the installation of the salt solution. Therefore, the composition 1 is significantly less irritating to the bladder than the current standard commercial composition valrubicin. Fig.2 illustrates graphically the inflammation of the urinary bladders of rats (animals) in the instillation Valstar® dilution with saline 1:2,75 compared with compositions 1 (dilution 1:2,75) and 8 (not divorced). While composition 1 is significantly less annoying (p=0.007) than the standard composition Valstar®, composition 8, though less annoying than the standard composition was not statistically significantly different from the composition Valstar® against inflammation. Fig.3 illustrates a comparison of compositions 4, 9, 11 and 12. While the absolute values appeared to vary from sample to sample, the differences are probably not statistically significant. In Fig.2 and 3, the concentration valrubicin approx what were approximately the same in all installations in the bladder solutions. For example, Valstar® and composition 1 with a dilution of 1:2,75, and undiluted composition 4, 8, 9, 11 and 12 all had a theoretical concentration valrubicin of approximately 11 mg/ml of the Present description is not limited by the specific embodiments described in this application. Can be made many modifications and variations without leaving the scope and essence of the invention, which is obvious to the person skilled in the art. In addition to the listed herein methods and devices specialist in this area, based on previous descriptions, will be apparent functionally equivalent methods and devices that are within the description. Understood that such modifications and variations fall within the scope of the attached claims. The present description is limited only by the attached claims along with the full range of equivalents, which are indicated in the claims. It should be understood that this description is not limited to particular methods, reagents, compounds, compositions or biological systems, which can of course vary. It should also be understood that the terminology used herein is intended solely for the purpose of a particular description, and is not intended to limit.

In addition, there is de properties or aspects of the descriptions described by Markush groups, specialists in this field will be clear that the description will also be given by any individual member or subgroup of members of the Markush group.

The specialist will be clear to any or all of the purposes specifically through the submission of written descriptions that everything described in this document intervals also cover any or all possible subinterval and combinations of these subintervals. Any given interval can be easily recognized as sufficiently describing and enabling the same interval to get, at least equal halves, thirds, quarters, fifths, tenths, and so on, as a non-limiting example, each interval discussed in this paper can easily fall into the bottom third, middle third and upper third, etc. Also a specialist in this field will be clear that all expressions such as "to", "at least", "over", "less than" and the like include the number and denote intervals that can later get into subinterval, as discussed above. Finally, as will be clear to the person skilled in the art, the interval includes each individual member. Thus, for example, a group containing 1-3 cells, refers to groups containing 1, 2 or 3 cells. Similarly, the group containing 1-5 cells, about who appoints group, containing 1, 2, 3, 4, or 5 cells, and so forth.

While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be obvious to experts in this field. Various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to limit, with a real part and an entity that is specified by the claims.

1. Pharmaceutical composition for treating bladder cancer in a unit dosage form for intravesical administration by instillation containing
(1) an effective amount valrubicin and
(2) dimethyl sulfoxide, and either
(3A) one or more substances selected from the group consisting of trimethylchitosan, mono-N-carboxymethylchitosan, N-diethylethylene, sodium katrinasacay, cytochalasin, IL-1, polycarbophil, carbopol R, N-sulfate-N,O-carboxymethylchitosan, toxin, Zonula occludens, 1-Palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine or a mixture of any two or more of these compounds in the amount of 1-15 wt.% volume dosage forms or
(3b) polyethoxysiloxane castor oil, where
polyethoxysiloxane castor oil and dimethyl sulfoxide represented in equal numbers.

2. The pharmaceutical composition under item 1, where the effective amount valrubicin is about 5-100mg/ml, about 10-90 mg/ml, about 15-80 mg/ml, about 20-70 mg/ml, about 25-70 mg/ml, about 30-60 mg/ml, about 35-50 mg/ml, or about 35-45 mg/ml

3. The pharmaceutical composition according to p. 1, additionally containing one or more amplifiers chemical penetration, selected from the group consisting of: ethanol, ISO-propanol, dimethylacetamide, dimethylformamide, decelerated, 2-pyrrolidone, N-ethyl-2-pyrrolidone, capric acid, linoleic acid, urea, sodium dodecyl sulfate, sodium lauryl sulphate and mixtures of two or more of these compounds.

4. The pharmaceutical composition under item 1, where the effective amount valrubicin and dimethyl sulfoxide enough for the treatment of bladder cancer.

5. The pharmaceutical composition according to p. 1, where polyethoxysiloxane castor oil is cremophor.

6. The pharmaceutical composition under item 5, where the cremophor and dimethyl sulfoxide represented in equal numbers.

7. The pharmaceutical composition according to p. 1, additionally containing an ionic or non-ionic surfactant, polyvinylpyrrolidone, alginates, polyacrylic acid or a mixture of any two or more of them.

8. The pharmaceutical composition according to p. 7, where ionic and non-ionic surfactants are polyoxyethylene derivatives of castor oil, block copolymers of ethylene oxide and of propylene oxide, esters of sorbitol and fatty acids or mixtures of any two or more of them.

9. The pharmaceutical composition under item 8, wherein the polyacrylic acid are carbomer R, carbomer 940, carbomer 941, carbomer R, carbomer 980, carbomer 1342, polycarbophil, polycarbophil calcium or a mixture of any two or more of them.

10. Pharmaceutical composition for the treatment of bladder cancer, comprising: liposomal dosage form for intravesical administration by instillation containing an effective amount included in the liposome valrubicin; where the liposome containing at least one forming a liposome substance selected from the combinations consisting of phosphatidylcholine, phosphatidylethanolamine, sphingolipids with oleic acid or diglycerides succinate.

11. A method of treating bladder cancer, including intravesical introduction by instillation of a pharmaceutical composition under item 1.

12. A method of treating bladder cancer, including intravesical introduction by instillation of a pharmaceutical composition according to p. 10.



 

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FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to urology and neurology, and can be used for selection of medication for treating hyperactivity of urinary bladder in men. For this purpose rectal ultrasound Dopplerographic examination of vessels of prostate gland and urinary bladder neck is performed before and 1 hour after pharmaco-test successively with selected medications of α-adrenolitics, m-cholinolitics and with their combination. Interval between examinations constitutes 2-4 days. After that, integral percentage of increase of peak rate of blood flow in vessels of prostate gland and urinary bladder neck after pharmaco-test is calculated. Medication, which causes maximal integral percentage of increase of blood flow rate after pharmaco-test, is selected for treatment.

EFFECT: method ensures increased accuracy of selection of medication for treating urinary bladder hyperactivity in men with reduction of its trauma, as well as prevention of side effects of therapy and inefficiency of particular medications.

6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of the following general formula [1a], wherein R1 represents (1) a hydrogen atom, (2) C1-C6alkyl group, (3) C2-C6alkenyl group, (4) C2-C6alkynyl group, (5) C1-C6alkoxygroup, (6) hydroxyC1-C6alkyl group, (7) C1-C6alkoxy(C1-C6)alkyl group, (8) -CONR11R12, wherein R11 and R12 are identical or different, and each represents a hydrogen atom or C1-C6alkyl group, (9) phenyl group or (10) a five-member heteroaryl group which contains at least one heteroatom specified in a group consisting of a nitrogen atom and oxygen atom, and which may be substituted by C1-C6alkyl group; R2 represents (1) a halogen atom, (2) C1-C6alkyl group, (3) hydroxy group or (4) C1-C6alkoxy group; p is equal to 0, 1, 2 or 3; X represents a carbon atom or nitrogen atom; m1 is equal to 0, 1 or 2; m2 is equal to 0 or 1; the spiro ring AB may be substituted by 1-5 identical or different, specified in a group consisting of (1) hydroxy group, (2) C1-C6alkyl group, (3) C1-C6alkoxygroup and (4) oxo group; n1 is equal to 0, 1, 2, 3 or 4; n2 is equal to 1, 2, 3 or 4; n3 is equal to 0, 1 or 2, provided n2+n3 is equal to 2, 3 or 4; and a bond presented by the symbol means a single bond or a double bond, provided the three adjoining carbon atoms forms no allene bond presented by formula: C=C=C, or a pharmaceutically acceptable salt thereof.

EFFECT: invention refers to a pharmaceutical composition possessing GPR40 agonist activity, to a GPR40 agonist drugs; to a hypoglycemic agent stimulating insulin secretion on the basis of the above compounds.

45 cl, 42 tbl, 120 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: bladder is released, washed with distilled water, and a drug solution is introduced therein. An intrabladder electrode representing a catheter provided with a cylinder on its proximal end and three tips on its distal end, as well as with an electrical conductor with its distal end coupled with a current source. One of the tips is used to fill the cylinder with air or physiological saline, and another one - to introduce drug substances, and the electrical conductor is wired through the third tip. On a proximal end of the catheter, there are window openings for liquid injection and ejection from a bladder cavity. At a level of these openings, inside of the catheter, there is a steel guide presented in the form of a symmetrical single spiral wound with turns touching of the diametre matched with an internal diametre of the catheter, and of the length 1/3 exceeding the length of said openings. An external electrode is presented in one layer of pull-ups made of a combined cloth consisting of elastane, wool and metal in the relation of 1:16:16. The electrode is processed by a conducting gel used to coat pelvic and perineal regions.

EFFECT: improved drug penetration into bladder tissues, including in patients with decreased physiological volume of bladder ensured by more tight adherence of the external electrode to the pelvic and perineal regions and increased skin current conductivity, eliminated direct contact of the intrabladder electrode with a bladder mucosa, avoiding injuries of the bladder walls.

2 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention is referred to medicine, physiotherapy. The method involves taking radon baths and drinking radon water. Baths with mineral water of thermal radon sources of natural water temperature approximately 38°C (radon water) are taken. Radon bath is taken for two days running followed by the one-day pause. Duration of the first procedure is 5 minutes, of the second one - 8 minutes, one the third one - 10 minutes. All the following procedures are 15 minutes long. 10-15 Baths are taken in total. The therapy is combined with keeping diet No.7b. Before noon, two hours after breakfast, the patient moderately drinks radon water 200 ml. On of the running bath-taking days, gynaecologic irrigations of radon water are prescribed for 15 minutes. On the other day mud applications on the underbelly are used during afternoon. The baths are combined with a detensor-therapy. During afternoon, two hours after dinner, the patient moderately drinks radon water 200 ml and takes a bath with radon water; then a resonant-acoustic fluctuations procedure follows. The bath is followed by a resonant acoustic oscillation procedure follows. On the bath-free days, intestinal lavage is prescribed before noon. During afternoon, 'Cedar Barrel' mini-phyto-sauna with deer-breeding antler products is applied.

EFFECT: method stimulates reparative processes, improved patient's quality of life, prolongs remission.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of invention refers to medicine, namely to oncology, and can be used in treating cancer in a patient. The method involves administering at least one encapsulated chemotherapeutic agent, and at least one amphiphilic block copolymer in this patient. What is also presented is a composition, a kit for treating cancer in the patient and using the amphiphilic block copolymer.

EFFECT: group of inventions provides potentiating the encapsulated chemotherapeutic agent by stimulating the active chemotherapeutic agent release from liposomes by the use of the amphiphilic block copolymer, which is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, in the composition.

10 cl, 11 dwg, 3 tbl, 4 ex

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